Manufacture of salts of phenolphthalic acid and its derivatives.



'. derivatives, these therefore the same.

rymg out the invention,

; STATES MARSHALL, OF

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1,071,321. llp'm'awing.

To all whom it may concern:

Be it known that we, PHILIP A. Korea, a citizen ofthe United States, residing at 1? West "a citizen of the United States, residing at Philadelphia, county of Philadelphia, State of Pennsylvania, have invented certain new and useful 'Im rovements in Manufacture of Salts of P 'enolphtha-lic Acid and Its Derivatives; and we do hereby declare the following to be clear, and exact description of the invention, such-as will enable others skilled in the art to which it appertains to make and use Our invention relates to the production of isolated salts of phenolphthalic acid and its isolated salts finding useful employment'as therapeutic agents and being particularly adapted for use as laxa-v tives by administration either in the usual way o'rby subcutaneous injection.

Inso far as we are aware, salts of heholphthalic acid andits derr'nrativesv ave not heretofore been isolated, and it will be understood that our invention and the claims formin'ga part of this specification and based upon the following disclosure are intended to have a correspondiugly fundamental orgeneric scope. In carthe methods that found feasible for obtaining the we have isolation of" the salts we prefer to direct,

or from a suitable in the first instance, to the production of the tri-basic salts ofthe acid or its derivaand to thereafter produce the mono- .tained. For the production of" the tri-basic salt, we. may proceed from phenolphthalein I derivative of {he nolphthalein such as" he chlor or br'om derivative.

As a typical illustration of the method of producing the tri-basic salt from phe- +KOH I As will the potassium a full,

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nel phtha'lein ample: 30 grams be moistened with water to form a paste, and is then treated with a saturated aqueous solution containing lhtl grams of potassium hydrate.

"s mncautn of Letters r am Fatented Aug; 26,1913. Application ma Ziecember 29, 1am. serial 599,312. p

we may givethe'following ex 7 of phenolphthalein may The mixture 1s then warmed at a temperature of say 80 G.- and preferably at a reduced pressure, say a pressure corresponding to 30 millimeters of mercury, for the purpose of concentrating the solution by driving 011' such percentage of its moisture as will fpermit' the desired crystallization.

The solution is then cooled to about zero C'. and is allowed to stand for say twelve hours out of contact with the air and moisture, so as to avoid'the formation of carbonates by reason of. any carbon di-oxid present in the air and to preventdecomposition of. the crystals already-formed. The precipitate is then filtered oil, as, for instance, through asbestos fiber, or eentrifugally,

washed, first wi cold water and then witha' mixture of equal volumesof ethyl alcohol and benzene, pref- 70 then further, continued, preferof ethyl" alcohol erably at a C. The washing is ably with a mixture'of 30% in'benzol, and finally with ethyl ether. The washed precipitate, consisting of the tribasic salt of phenolphthalic acid, is then temperature below 10 and is then th a small-volume of ice" dried in vacuol It will, of course, be understood that the purpose of washing the precipitate is to get ri'dof the mother liquor in which the crystals are formed and to obtain the dry product with as little subsequent decomposition or alteration as is possible. other suitable or lixiviating operation adapted to the purpose may be employed within the knowledge of those skilledin the The tri-basic salt produced by-the treat- ,ment of the phenolphthalein, as above described, with the potassium hydrate will be the tri-basic'potassium salt, obtained in accordance with the following formula "to of the-best results;

.cess, which is preferable forithe production trated under the same conditions as to tom-- perature and reduced ressure hereinbefore specified until crystallization in the mother liquor takes place.' In thisinstance, it is not necessary to 'permitthe solution to stand for any given period of time but it may be at once cooled and filtered, as'before. It may then be Washed with say of alcohol in benzol until the crystals, which have a tendency to stick together, form a loose The tribasic calcium phenolphthalate' thus basiccalcium phenolphthalate, according to' the following formula: 40

As hereinbefore indicated, instead of employing phenol'phthalein itself asthe starting point of the operationwe may proceed from one of its derivatives, for which purpose we usually prefer to employ either the chlor derivative or thebrom derivative, on account of the high therapeutic value of the salts produced therefrom. For instance, the chlor derivative known as phenoltetrachlorphthalein may be treated to producelanyof the alkaline tri-basic salts by substituting it, in the operations hereinbefore described, for phenolphthalein itself; and, in general, the same is true of other phenolphthalein derivatives, as, for'instance, the esters and others.

- From the tri-basic salts produced in acmass. The washing is then com leted with pure benzol or some other like so stance not miscible in water and containing none of the hydro'xyl group. r v

In like manner other of the alkaline tri: basic salts may be .obtained b treating phenolphthalein with saturated aqueous solutions of other hydrates, as lithium hydrate, calcium hydrate, and the like; but the employment of these other hydrates is less desirable from the fact that they are but slightly soluble in water and therefore require a greater. amount of concentration for the crystallizing out of the salt produced. Thus by treating phenolphthalein with calcium hydrate in excess, we have cordance with the procedures hereinbefore basic salts of phenolphthalic acid and-its do rivatives. This may be conveniently accomplished by treatin the tri-basic salt in the 1 presence of cold solute alcohol or the 1 presence of acetone,- with a weak acid for the purpose of decomposing the tri-ba'sic salt producing'the mono-basic salt which is soluble in the alcohol or acetone. Where absolute alcohol is employed for this purpose it will be convenient to employ as the weak' acid an alcoholic or" ethereal solution of fatty acids (for example, stearic acid, or oleic acid) whose soaps are nsoluble in alcohol, and then precipitating out the mono basic'salt with ethyl ether, benzin, ligroin,

or other suitable ethereal solvents; whereupon the mono-basic salt is filtered and dried as before. Where carbonic acid isemployed' as the weak acid, the resulting carbonates are insoluble in the acetone or in the alcohol employedand are precipitated out together with such portion of the, tri-basic salt as may remain undecompos'ed; After filtering ed the insoluble matter, a sulficient amount of ethyl ether or some other suitable precipitating liquid is added to the mono-basic salt solution until the mono-basic salt is precipitated out, whereupon it is filtered and washed. Where, for instance, the monobasic' salt is produced'fr'om'the tri-basic salt of a phenolphthalio acid derivative, the oporation may be ex ress'ed by means'of the" following general -ormula, to wit specified, we may likewise produce the mono basic form or in the mono-basic form, has

out the resulting phthalate by evaporation in cacao; substantially as described.

' dooK wherein R represents hydrogen or any substitute for hydrogen as, for instance C H C H etc., and wherein HF represents any of the fatty acids.

It will be understood, therefore, that the production of the mono-basic salt from the tri-basic salt may be practised, in accordance with our invention, an any reaction represented by this general formula.

Our phthalate product, whether in the trias its ultimate basis phenolphthalein, either as such, or in some of its derivatives, as hereinbefore described. In this sense, itis both generically and specifically new. in so far as we are aware.

, What we claim is:

1. The method of obtaining pht-halates from phenolphthalein and its derivatives, which consists in subjecting the same to the action of an alkali until a phthalate is produced, and separating it out in solid form; substantially as described.

2. The method of obtaining phthalates from phenolphthalein and its derivatives, which consists in subjecting the same to the action of an aqueous solution of alkali until a phthalate is produced, and crystallizing'out the resulting phthalate; substantially as described. i 3. The method of obtaining phthalates from phenolphthalein and its derivatives, which consists in subjecting the same to the action of an aqueous solution of alkali until a, plithalate is produced, and crystallizing 4:. The method of obtaining phthalates from phenolphthalein and its derivatives, which consists in subjecting the same'to the action of an aqueous solution of alkali until a phthala-te is produced, erystallizing out the resulting phthalate, washing the crystals to remove free alkali, and drying them; substantially as described.

5. The method of obtaining phthalates from phenolphthalein and its derivatives,

which consists in subjecting the same to the action of'an alkali until a phthalate is produced, separating it out in solid form, and finally converting it into the mono-basic salt; substantially as described.

6. The method of obtaining phthalates from phenolphthalein and its derivatives, which consists in subjecting the same to the action of an alkali until a phthalateis produced, separating it out in solid form, and. finally converting it into the monmbasicsalt by dissolving it in a non-aqueous solvent in which alkaline carbonates and alkaline salts of weak acid are insoluble, subjecting it to the action of a weak acid, and precipitating by means of an ethereal solvent; substan tially as described.

7 An isolated monobasic phenolphthalate; substantially as described.

8. An isolated monobasic alkaline phenol phthalate; substantially as described.

In testimony whereof, we aiiix our signatures in presence of two witnesses.

PHILIP A. KQBER. JOHN THEODORE MARSHALL.

\Vitnesses:

. CLAYTON McELRoY,

LIZZIE MOGEN.

upon the application of Philip A. Kober, of

the printed specification requiring correction formula, symbols appearin at the end of that the same may conform to the record of [SEAL] It is hereby certified that in Letters Patent No. 1,071,321, granted August 26, 1913,

Hastings-upon-Hudson, New York. and

John Theodore Marshall, of Philadelphia, Pennsylvania, for an improvement in The Manufacture of Salts of Phenolpht-halic' Acid and its Derivatives," errors appear inas follows: Page 1, line 73. for the word benzol read benzene; page 3, lineS, for the article an" read in: and same page,

the lines, for OK" read (III in both places; and that the said Letters Patent should be read with these corrections therein the case in the Patent Ofiice.

Signed and sealed this 30th day of September, A. D., 1913.

R. T. FRAZIER, Acting Commissioner of Patents.

basic form or in the mono-basic form, has

out the resulting phthalate by evaporation in cacao; substantially as described.

' dooK wherein R represents hydrogen or any substitute for hydrogen as, for instance C H C H etc., and wherein HF represents any of the fatty acids.

It will be understood, therefore, that the production of the mono-basic salt from the tri-basic salt may be practised, in accordance with our invention, an any reaction represented by this general formula.

Our phthalate product, whether in the trias its ultimate basis phenolphthalein, either as such, or in some of its derivatives, as hereinbefore described. In this sense, itis both generically and specifically new. in so far as we are aware.

, What we claim is:

1. The method of obtaining pht-halates from phenolphthalein and its derivatives, which consists in subjecting the same to the action of an alkali until a phthalate is produced, and separating it out in solid form; substantially as described.

2. The method of obtaining phthalates from phenolphthalein and its derivatives, which consists in subjecting the same to the action of an aqueous solution of alkali until a phthalate is produced, and crystallizing'out the resulting phthalate; substantially as described. i 3. The method of obtaining phthalates from phenolphthalein and its derivatives, which consists in subjecting the same to the action of an aqueous solution of alkali until a, plithalate is produced, and crystallizing 4:. The method of obtaining phthalates from phenolphthalein and its derivatives, which consists in subjecting the same'to the action of an aqueous solution of alkali until a phthala-te is produced, erystallizing out the resulting phthalate, washing the crystals to remove free alkali, and drying them; substantially as described.

5. The method of obtaining phthalates from phenolphthalein and its derivatives,

which consists in subjecting the same to the action of'an alkali until a phthalate is produced, separating it out in solid form, and finally converting it into the mono-basic salt; substantially as described.

6. The method of obtaining phthalates from phenolphthalein and its derivatives, which consists in subjecting the same to the action of an alkali until a phthalateis produced, separating it out in solid form, and. finally converting it into the monmbasicsalt by dissolving it in a non-aqueous solvent in which alkaline carbonates and alkaline salts of weak acid are insoluble, subjecting it to the action of a weak acid, and precipitating by means of an ethereal solvent; substan tially as described.

7 An isolated monobasic phenolphthalate; substantially as described.

8. An isolated monobasic alkaline phenol phthalate; substantially as described.

In testimony whereof, we aiiix our signatures in presence of two witnesses.

PHILIP A. KQBER. JOHN THEODORE MARSHALL.

\Vitnesses:

. CLAYTON McELRoY,

LIZZIE MOGEN.

upon the application of Philip A. Kober, of

the printed specification requiring correction formula, symbols appearin at the end of that the same may conform to the record of [SEAL] It is hereby certified that in Letters Patent No. 1,071,321, granted August 26, 1913,

Hastings-upon-Hudson, New York. and

John Theodore Marshall, of Philadelphia, Pennsylvania, for an improvement in The Manufacture of Salts of Phenolpht-halic' Acid and its Derivatives," errors appear inas follows: Page 1, line 73. for the word benzol read benzene; page 3, lineS, for the article an" read in: and same page,

the lines, for OK" read (III in both places; and that the said Letters Patent should be read with these corrections therein the case in the Patent Ofiice.

Signed and sealed this 30th day of September, A. D., 1913.

R. T. FRAZIER, Acting Commissioner of Patents. 

